The NMTrypI concept is based on the development of innovative drug leads including a mechanism-based combination of a known and investigational drug and dual targets inhibition by using a common drug discovery platform (Figure 1) established by experts in their respective fields from SMEs (ESP, HITS, Tydock, Hypha) and the public research sector in Europe and in disease-endemic countries (UNIMORE and UNISI-Italy, BNI-Germany, UCM-Spain, IBMC-Portugal, NHRF-Greece, CNPEM-Brazil NCR-Sudan). The innovative concept is reinforced by the identification of preclinical biomarkers enabling the proteomic profiling of the compound to understand the mechanism of action (MoA biomarker) and to detect the efficacy of the lead candidate (pharmacodynamic biomarkers). Four innovative compound classes will be studied in the NMTrypI project: - Miltefosine derivatives, ring-substituted and hybrid derivatives of the known drug. - Folate pathway targeting drugs, which are Pteridine derivatives and Thiazole/thiadiazole derivatives. - And finally natural compounds from fungi and plants where the 50% is expected to provide novel compounds. A highly interdisciplinary approach based on an iterative lead optimization concept (Figure 2) will be used to optimize these compounds against trypanosomatids. The drug leads trigger mechanisms that are associated with protozoa virulence and pathogenicity. The new NMTrypI platform will perform the screening of compound libraries, lead development, testing in mice, hamsters and dogs as a reservoir of the visceral leishmaniasis disease as well as toxicology and safety testing (in vitro against cellular types and in vivo in animals) to overcome current limitations in anti-trypanosomatid therapy. The major strength of the NMTrypI consortium lies in the complementary expertise in lead optimization (molecular modeling, synthetic chemistry, X-ray crystallography), pharmacokinetic (PK) and pharmacodynamic (PD) studies on known and validated early PK models, drug delivery optimization of the candidates, parasite models strains and clinical isolates (not freshly collected) testing in high throughput and normal scale methods, drug target validation of the best leads in the parasites animal evaluation from mice to dogs, biomarker studies through proteomic and functional genomic profiling of model strains and clinical isolates (not freshly collected), drug resistance studies in parasites (only for drug leads selection) and in vivo for the best candidates.
|Titolo:||New Medicine for Trypanosomatidic infections-NMTrypI (NMTrypI)FP7-HEALTH-2013-2.2.4-2: Drug development for neglected parasitic diseases, grant agreement no 603240.|
|Autori:||Maria, Paola Costi; Stefania, Ferrari; Glauco, Ponterini; Luca, Costantino; Gaetano, Marverti; Rosaria, Luciani; Pasquale, Linciano; Donatella, Tondi|
|Data di pubblicazione:||2014|
|Appare nelle tipologie:||Partecipazione a progetti di ricerca|
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